1. Field of the Invention
The present invention relates to the improvement of surgical techniques and tissue-protective surgical solutions.
2. Discussion of the Prior Art
Adhesions of the tissues involved in surgery occasioned by manipulative trauma of the tissue surfaces during the surgery and other causes such as drying and ischemic trauma constitute one of the most serious post-operative complications of surgical procedures.
Although a variety of techniques have been proposed to reduce adhesions, the problem continues to plague the art and seriously compromise even the finest and most scrupulously performed surgeries. Prior attempts to alleviate the problem and the disappointing results attendant are described by Davis et al in Surgery, Vol. 2, p. 877 (1937); Gozalez, Surgery, Vol. 26, p. 181 (1949); Hunter et al, J. Bone Joint Surg., Vol. 53A, p. 829 (1971); Ellis, Surg. Gynecol. Obst., Vol. 133, pp. 497-511 (1971); Lindsay et al, In Verdan, C. (ed.); Tendon Surgery of the Hand, London, Churchill Livingstone, pp. 35-39 (1979); Potenza, J. Bone Joint Surg., Vol. 45A, p. 1217 (1963); Verdan, J. Bone Joint Surg., Vol. 54A, p. 472 (1972); St. Onge et al, Clin. Orthop., Vol. 148, pp. 259-275 (1980); Thomas et al, Clin. Orthop., Vol. 206, pp. 281-289 (1986); Weiss et al, Bull. Hosp. Jt. Dis. Orthop. Inst., Vol. 46(1), pp. 9-15 (1986).
Goldberg et al [Arch. Surg., Vol. 115, pp. 776-780 (1980)] describe the use of certain hydrophilic, polymeric solutions (Povidone polyvinylpyrrolidone K-30 PVP, and dextran) to coat tissue exposed to drying and/or manipulative peritoneal trauma, as well as the surgical articles and the like, which contact the tissue before and during surgery to prevent adhesions. Although the materials and methods of Goldberg et al showed some improvement over other research studies in which hydrophilic, polymeric solutions were used to attempt to reduce the incidence of surgical adhesions, there still exists significant need for improvement.
A distinct disadvantage associated with the materials and methods of Goldberg et al and other prior art which has shown some benefit is the required use of highly concentrated solutions of the polymeric materials which makes practical use in surgery very difficult. Concentrated polymeric solutions (greater than about 10-15%), for example, the 25% PVP and dextran solutions used by Goldberg et al, become sticky due to drying during surgery on the surfaces of tissue, surgeons' gloves, instruments, and the like. This can seriously interfere with normal surgical procedures. High concentrations of PVP (K-30 molecular weight about 40,000) and dextran (molecular weight about 300,000) were required to achieve even some degree of tissue protection. Many studies prior to the report of Goldberg et al used lower concentrations of PVP, dextran or other water-soluble polymers which were even more ineffective. For example, Ellis [supra] has stated that "use of PVP was accompanied by a slightly greater incidence of adhesions" in a rat peritoneal adhesions study. He also states that because "such macromolecular solutions as plasma or dextran are known to be absorbed rapidly through functional lacunas on the under surface of the diaphragm" and "[i]t is therefore probable that any effect of PVP or any other macromolecular solution introduced into the peritoneal cavity could only be transitory." In the study by Berquist [Eur. Surg. Res., Vol. 9, p. 321 (1977)] using 10% dextran-70 (molecular weight 70,000) and 1% hyaluronic acid (molecular weight unknown), it was reported that there was "no difference between control and treated groups" for adhesions in rat and rabbit studies. Even attempts to use the relatively low molecular weight dextran-70 at very high concentrations (32%) based on suggestions of some beneficial effect in reducing genital tract adhesions in female rabbits [Neuwirth et al, Am. J. Obst. Gynecol., Vol. 121, p. 420 (1974)] have not proven very successful. A commercial 32% (w/v) solution of dextran-70 was introduced as a hysteroscopy fluid around 1984, but recent studies have shown "no effect in reducing adhesions" using 32% dextran [Hadick et al, Military Medicine, Vol. 152, p. 144 (1987)].
Moreover, the use of such high concentrations may increase the expense of the surgical solutions and poses problems in preparing, purifying, stabilizing and storing solutions of such highly concentrated and often viscous solutions. For example, 32% dextran tends to crystallize "when subjected to temperature variations or when stored for long periods" [data sheet for commercial 32% dextran-70 solution].
Although the studies reported by Goldberg et al indicated some modest improvement in preventing adhesions using 25% PVP (molecular weight 40,000) and a slight improvement with 25% dextran (molecular weight 300,000) even using a surgical method involving coating of tissues and surgical implements before surgical manipulation, the materials and surgical solutions used were clearly impractical for clinical use in surgery.
In patent application Ser. No. 07/555,377 filed Jul. 19, 1990, now U.S. Pat. No. 5,080,893, there are described improved methods for preventing surgical adhesions in tissue by manipulation thereof during surgery comprising coating tissue surfaces involved in the surgery and/or the surfaces of surgical articles which contact the tissue surfaces during the surgery with an aqueous solution of a hydrophilic, polymeric material selected from the group consisting of water-soluble, biocompatible, pharmaceutically acceptable polypeptides, polysaccharides, synthetic polymers, salts and complexes thereof and mixtures thereof prior to manipulation of the tissue during the surgery, the improvement wherein the hydrophilic, polymeric material is of high molecular weight (greater than 500,000) and the solution contains from about 0.01% to about 15% by weight of the polymeric material.
The application further describes certain compositions, specifically adapted for coating the surfaces of tissues involved in surgery and preferably also the surfaces of articles which contact the tissue surfaces during the surgery to prevent surgical adhesions in the tissue by manipulation or drying thereof during surgery, consisting essentially of a pharmaceutically acceptable aqueous solution of a hydrophilic, polymeric material of high molecular weight (greater than 500,000) selected from the group consisting of pharmaceutically acceptable polypeptides, polysaccharides, synthetic polymers and salts and complexes thereof and mixtures thereof. Where the polymeric material is a polysaccharide, solutions according to the invention containing from about 0.01 to less than about 1% by weight of the polysaccharide have been found to be highly advantageous. Where the polymeric material is a polypeptide or synthetic polymer, solutions according to the invention containing from about 0.01 to less than about 15% by weight thereof may be employed.
An additional embodiment of the invention described therein comprised surgical articles, surfaces of which are adapted for contacting tissue surfaces during surgery having a coating thereon formed from a composition described above.
Surgical adhesions, however, are only one of the several types of complications which arise from the damage inflicted to tissue during surgical procedures. In addition to the formation of post-operative adhesions, tissue trauma during surgery can lead to a host of other potentially serious complications during and following surgical procedures, including:
(1) excessive blood vessel damage with increased bleeding during surgery and with greater risk of postoperative hemorrhage; PA1 (2) enhancement of (acute) post-operative inflammation with prolongation of healing and damage to adjacent healthy tissues, as well as increased potential for chronic prolonged inflammation with associated secondary complications, pain, and the like; PA1 (3) compromised wound healing with excessive scar tissue, of particular importance in orthopedic and plastic surgery; PA1 (4) damage to organs and tissues which can result in impaired organ function, i.e., kidneys, liver, heart, lungs, and the like; PA1 (5) blood vessel damage which can reduce blood supply with partial ischemia of muscle tissues and organs, leading to compromised function of muscle and vital organs, which is a life-threatening situation for heart muscle damage; and PA1 (6) increased susceptibility to acute and chronic infections due to preferential adherence and growth of pathogens on damaged tissue sites (post-operative staph and pseudomonas infections) with increased difficulty in treatment, slower recovery and greater chance of life-threatening systemic sepsis. PA1 (a) the polymeric material is (1) a substantially water-soluble polymer having at least one C.sub.n F.sub.2n+1 substituent wherein n.gtoreq.4, having a molecular weight of less than about 60,000; (2) a pharmaceutically acceptable salt or complex thereof; or (3) mixtures thereof; and PA1 (b) the concentration of the aqueous solution of the polymeric material is in the range of from about 0.1% to about 5.0% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the tissue. PA1 (a) the polymeric material is (1) a substantially water-soluble polymer having at least one C.sub.n F.sub.2n+1 substituent wherein n.gtoreq.4, having a molecular weight of less than about 60,000; (2) a pharmaceutically acceptable salt or complex thereof; or (3) mixtures thereof; and PA1 (b) the concentration of the aqueous solution of the polymeric material is in the range of from about 0.1% to about 5.0% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the tissue. PA1 (a) the polymeric material is (1) a substantially water-soluble polymer having at least one C.sub.n F.sub.2n+1 substituent wherein n.gtoreq.4, having a molecular weight of less than about 60,000; (2) a pharmaceutically acceptable salt or complex thereof; or (3) mixtures thereof; and PA1 (b) the concentration of the aqueous solution of the polymeric material is in the range of from about 0.1% to about 5.0% by weight, the molecular weight and concentration having values such that the aqueous solution is capable of providing wet coatings on the tissue.
All of the above tissue damage related complications can result in longer hospitalization, patient discomfort, greater risk of morbidity and mortality, greater incidence of re-hospitalization and corrective surgery with associated patient risks, and higher health care costs.
Desiccation and abrasion tissue damage during surgery can lead to a variety of pathological surgical and postoperative complications. Damage due to desiccation and abrasion of the ovaries often results in formation of a thin fibrous membrane over the surface of the organ. Often this membrane is difficult to see with the unaided eye, yet it can act as a physical barrier to prevent transport of an egg to the Fallopian tube, thus preventing fertilization.
Prosthetic devices and implants such as heart valves, ventricular assists, vascular grafts, ligaments, tendons, corneas, skin grafts, muscle grafts and the like which are derived entirely or in part from animal or human tissue or organs are subjected to handling and manipulation in the normal course of harvesting, processing, manufacturing, shipping and storage of prostheses. Some specific examples of such bioprostheses include, but are not limited to, porcine heart valves, fetal tissue derived vascular grafts (e.g., from umbilical tissue), fetal neurological tissue, electrically activated muscle blood pumps (e.g., ventricular assist devices), and the like. The manipulation of these tissue derived bioprostheses and organ transplants can damage tissues, e.g., by desiccation or abrasive trauma, and thereby adversely affect in vivo biophysical or biochemical properties and reduce the safety and efficacy of the bioprosthesis or organ transplant. Organ and tissue transplants such as hearts, lungs, kidneys, livers, corneas, tendons and the like can be similarly damaged by the normal manipulation that occurs with harvesting, storing, preparing, processing, shipping and implanting organs, tissues or composite bioprostheses into recipient patients.
It is an object of the present invention to provide an improved method of preventing surgical adhesions during surgery.
It is another object of the present invention to provide improved compositions and methods for protecting tissue and preventing tissue damage in surgery.
It is an additional object of the present invention to provide improved methods and compositions for protecting human and animal derived tissues and organs during the manipulations that occur during harvesting, processing, storing, shipping and implantation thereof from trauma and damage which can result in impaired organ or tissue function or induce undesirable biological behavior.
Finally, it is a further object of the present invention to provide improved compositions and methods for protecting those parts of bioprostheses derived from animal or human tissues or organs from trauma and damage during the harvesting thereof and the manufacture, processing, storing, manipulation, shipping and implantation of the bioprosthesis, which trauma or damage could result in impaired bioprosthesis function or induce undesirable biological behavior.